DRESS/DIHS is one of the most serious delayed-type adverse drug reactions encountered in clinical medicine. It is characterized by a widespread skin eruption, fever, systemic inflammation, involvement of internal organs such as the liver, hematologic abnormalities including atypical lymphocytes, and, in many cases, reactivation of human herpesvirus 6, or HHV-6. The syndrome typically develops two to six weeks after exposure to the culprit drug, a latency that distinguishes it from immediate hypersensitivity reactions. Mortality is significant, particularly when liver involvement is severe, and recognition depends on scoring systems such as RegiSCAR that integrate rash morphology, fever, lymphadenopathy, blood count abnormalities, organ involvement, and viral reactivation. In immunocompetent patients, the diagnostic constellation is usually recognizable, but the syndrome’s presentation can be substantially altered in patients whose immune systems have been profoundly suppressed by chemotherapy.

CPX-351, marketed as Vyxeos, is a dual-drug liposomal encapsulation designed to optimize the synergistic molar ratio of cytarabine to daunorubicin and to prolong their exposure within the plasma. It is approved for treatment-related acute myeloid leukemia and acute myeloid leukemia with myelodysplasia-related changes, populations in which intensified traditional induction regimens carry prohibitive toxicity. Skin eruptions are common adverse events with CPX-351, and one of the most frequent cutaneous findings in these patients is toxic erythema of chemotherapy, or TEC, a benign and self-limited eruption that typically affects the hands, intertriginous areas, and trunk within days of drug exposure. Distinguishing TEC from an evolving DRESS/DIHS-like reaction is difficult, and the new case illustrates precisely how the two conditions can overlap in their earliest phases.

In the reported patient, the cutaneous story began with an early eruption localized to the intertriginous areas and trunk, a distribution and timing initially compatible with toxic erythema of chemotherapy. Had the eruption followed the usual course, it would have been expected to stabilize and resolve without intervention. Instead, the clinical picture deteriorated. The patient developed recurrent fevers, and the eruption progressed to generalized erythema covering more than 90 percent of his body surface area. Accompanying features included lymphadenopathy, the appearance of atypical lymphocytes in the peripheral blood, and elevation of liver enzymes, each of which is a recognized component of the DRESS/DIHS diagnostic framework. Taken together, these findings shifted the clinical suspicion away from benign toxic erythema and toward a systemic drug hypersensitivity syndrome.

Several laboratory investigations provided pivotal diagnostic clues. Most strikingly, quantitative polymerase chain reaction demonstrated a markedly elevated HHV-6 DNA level of 1.2 million copies per milliliter of blood. HHV-6 reactivation is considered a signature feature of classic DRESS/DIHS, occurring in the majority of typical cases, and its detection in this severely lymphopenic patient served as a strong corroborating marker of the syndrome. At the same time, the case defied several conventional expectations. The patient had severe chemotherapy-induced lymphopenia, there was no peripheral eosinophilia, skin histology revealed inconspicuous dermal eosinophils, and serum thymus and activation-regulated chemokine, known as TARC and often used as a biomarker of DRESS/DIHS, was at a normal level. The authors emphasize that these deviations are precisely what made the diagnosis so difficult, since eosinophilia and elevated TARC are among the criteria clinicians most commonly rely upon.

A skin biopsy provided additional support for the diagnosis. Histopathologic examination showed interface dermatitis with superficial perivascular lymphocytic infiltration, a pattern consistent with a delayed hypersensitivity reaction rather than the necrotic keratinocytes and eccrine involvement more characteristic of toxic erythema of chemotherapy. Interface dermatitis, in which lymphocytes attack the basal layer of the epidermis, is a histologic hallmark seen in many drug-induced eruptions, including DRESS/DIHS, and its identification helped consolidate the clinical and laboratory findings into a coherent diagnosis despite the absence of eosinophils in the dermal infiltrate.

Treatment with systemic prednisolone produced a rapid and convincing response. The patient’s fever resolved promptly, appetite improved, the extensive skin lesions began to heal, atypical lymphocytes disappeared from the circulation, and HHV-6 DNA became undetectable. The temporal relationship between corticosteroid initiation and the simultaneous resolution of inflammatory, cutaneous, and virologic abnormalities is characteristic of DRESS/DIHS and further reinforced the diagnostic conclusion. Importantly, the patient was subsequently able to proceed to conditioning therapy and umbilical cord blood transplantation, meaning that recognition and treatment of the hypersensitivity reaction did not derail his definitive leukemia management.

Attribution of the reaction to CPX-351 required careful weighing of alternatives, and the authors frame the association as possible rather than definitive. The temporal relationship between CPX-351 administration and the onset of the reaction was the principal basis for implicating the drug, but the authors explicitly note that toxic erythema of chemotherapy and concomitant medications represented important alternative considerations. Patients with acute myeloid leukemia typically receive multiple supportive agents, including antimicrobials, antifungals, and antivirals, several of which are themselves recognized causes of DRESS/DIHS. In addition, the leukemia itself and its complications can produce fever, rash, hepatic dysfunction, and lymphadenopathy. The heterogeneity of the clinical environment in hematology patients means that drug causality assessment in this population is intrinsically uncertain, and the report’s cautious language reflects this reality.

Beyond its immediate clinical message, the case carries broader implications for how DRESS/DIHS is understood and diagnosed. Classical descriptions assume a relatively intact immune system capable of mounting the full hypersensitivity phenotype, including expansion of drug-specific T cells, eosinophil recruitment through interleukin-5, and elevated TARC production by activated lymphocytes. A patient with profound chemotherapy-induced lymphopenia lacks the cellular substrate for many of these features, and the reported case demonstrates that the syndrome can nonetheless develop in this setting. This suggests that current diagnostic criteria, which award points for eosinophilia, atypical lymphocytes, and lymphadenopathy, may underdiagnose DRESS/DIHS in severely immunocompromised patients. The authors propose that HHV-6 reactivation may serve as a particularly valuable diagnostic marker when eosinophilia is absent, since viral reactivation appears to depend on mechanisms that can persist despite lymphocyte depletion.

The report also offers practical guidance for clinicians who treat high-risk acute myeloid leukemia with CPX-351. Skin eruptions during therapy should not automatically be dismissed as toxic erythema of chemotherapy, particularly when they progress beyond the typical distribution, persist or worsen after the expected time course, or are accompanied by recurrent fever, lymphadenopathy, hepatic enzyme elevation, or atypical lymphocytes. In such circumstances, measurement of HHV-6 DNA and consideration of a DRESS/DIHS-like reaction are warranted even in the face of severe lymphopenia and absent eosinophilia. Early recognition matters because untreated DRESS/DIHS can progress to fulminant hepatic failure and death, while timely systemic corticosteroids, as demonstrated in this patient, can produce rapid clinical improvement and allow the underlying leukemia treatment plan, including allogeneic transplantation, to continue on schedule. As CPX-351 use expands worldwide, the authors suggest that clinicians maintain heightened awareness that this liposomal chemotherapy regimen, like many other drugs, may in rare cases trigger systemic hypersensitivity, and that its cutaneous and systemic fingerprints may look different in the immunosuppressed host than in the patients in which the syndrome was first described.

Subject of Research: Possible CPX-351-associated DRESS/DIHS-like drug hypersensitivity reaction during severe lymphopenia in acute erythroid leukemia

Article Title: Possible CPX-351-associated drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome-like reaction during severe lymphopenia

Article References: Bamba, S., Kanda, J., Hada, M., Kubota, Y., Nakajima, S., Nomura, T., Fukutome, T., Tsuji, K., & Takaori-Kondo, A. (2026). Possible CPX-351-associated drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome-like reaction during severe lymphopenia. Annals of Hematology. https://doi.org/10.1007/s00277-026-07282-9

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07282-9

Keywords: CPX-351, DRESS, DIHS, HHV-6, acute myeloid leukemia, drug hypersensitivity, lymphopenia, skin eruptions, TARC, interface dermatitis, toxic erythema of chemotherapy, Annals of Hematology